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US6399299B1 - Amplified array analysis system - Google Patents

Amplified array analysis system Download PDF

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Publication number
US6399299B1
US6399299B1 US09/430,429 US43042999A US6399299B1 US 6399299 B1 US6399299 B1 US 6399299B1 US 43042999 A US43042999 A US 43042999A US 6399299 B1 US6399299 B1 US 6399299B1
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United States
Prior art keywords
specific binding
binding pair
enzyme
members
analytical system
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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US09/430,429
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English (en)
Inventor
Mark Norman Bobrow
Karl Edwin Adler
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Revvity Health Sciences Inc
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PerkinElmer Life Sciences Inc
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Priority to US09/430,429 priority Critical patent/US6399299B1/en
Priority to PCT/US1999/025616 priority patent/WO2000026409A1/fr
Priority to EP99971465A priority patent/EP1127166A4/fr
Assigned to PERKINELMER LIFE SCIENCES, INC. reassignment PERKINELMER LIFE SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ADLER, KARL EDWIN, BOBROW, MARK NORMAN
Priority to US10/123,713 priority patent/US20020110846A1/en
Application granted granted Critical
Publication of US6399299B1 publication Critical patent/US6399299B1/en
Priority to US11/741,548 priority patent/US8153367B2/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54306—Solid-phase reaction mechanisms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips

Definitions

  • This invention relates to analytical systems wherein arrays of at least one material such as oligonucleotides, DNA and/or RNA and/or fragments thereof, peptides, protein fragments, cell fragments, cells and tissues is disposed on a support member and is contacted with a mixture which may or may not include a material which includes binding pair members which bind to at least one of the materials comprising the array.
  • the invention relates to analytical systems of this type which further include an amplified reporter system that do not depend on layering.
  • a specific binding pair is a system wherein the two components share an affinity for each other so as to cause one of the components contained in a mixture of materials to bind to the other upon contact.
  • Either or both components of a specific binding pair may be organic or inorganic.
  • binding pairs are antibodies and antigens, nucleic materials such as DNA, RNA and fragments thereof, free nucleotides, metallic moieties and nucleic acids or proteins, biotin and avidin, folic acid-folate binding protein, sulfhydryls and sulfhydryl reactive groups such as maleimides and haloacetyl derivatives, amines and amine reactive groups such as succinimidyl esters and isothiocyanates, etc.
  • nucleic materials such as DNA, RNA and fragments thereof, free nucleotides, metallic moieties and nucleic acids or proteins, biotin and avidin, folic acid-folate binding protein, sulfhydryls and sulfhydryl reactive groups such as maleimides and haloacetyl derivatives, amines and amine reactive groups such as succinimidyl esters and isothiocyanates, etc.
  • Typical assays based upon the formation of specific binding pairs include a reporter system which provides a detectable signal indicative of the formation of a specific binding pair.
  • a reporter system which provides a detectable signal indicative of the formation of a specific binding pair.
  • one of the members of the pair can be provided with a label which can comprise a fluorescent material, a radioactive material, any other signaling moiety, or a material which is further reactive with another species to form a colored complex or some other such detectable reaction product.
  • the reporter system in these types of assays is commonly referred to as a layered-type system wherein successive layers of reagents such as labeled antibodies or nucleic acid probes are applied one after another in successive manipulation to generate a detectable signal.
  • arrays comprised of one or more differing materials such as oligonucleotides, DNA and/or RNA and/or fragments thereof, peptides, protein fragments, cell fragments, cells and tissues disposed upon a support body.
  • the various members comprising the array are each capable of forming a unique, specific binding pair with their appropriate counterpart, and such arrays have great utility for rapidly screening mixtures for the presence or absence of a large number of materials. Techniques for the fabrication of such arrays will be found, for example, in U.S. Pat. No.
  • the present invention incorporates an amplification system into an array-based analysis.
  • the system of the present invention may be utilized for the analysis of materials such as oligonucleotides, DNA and/or RNA and/or fragments thereof, peptides, protein fragments, cell fragments, cells and tissues.
  • the present invention provides a method for enhancing the sensitivity of array-based analytical assay systems which comprises a support member having at least one different first member of a specific binding pair affixed in an array thereupon, a mixture which may include at least one second member of a specific binding pair capable of binding to one of the first members so as to form a specific binding pair which is affixed to the support member, and a reporter system that produces a detectable signal indicative of the presence or absence of the specific binding pair on the support member wherein the reporter system comprises an amplified reporter system that is independent of layering.
  • FIG. 1 is a schematic illustration of a catalyzed reporter deposition system in accordance with the present invention
  • FIG. 2 is a schematic illustration of a further stage in the catalyzed reporter deposition system in accordance with the present invention
  • FIG. 3 is a further schematic illustration of a stage of the catalyzed reporter deposition system in accordance with the present invention.
  • FIG. 4 is a further schematic illustration of a stage of the catalyzed reporter deposition system in accordance with the present invention.
  • FIG. 5 is a further schematic illustration of a stage of the catalyzed reporter deposition system in accordance with the present invention.
  • FIGS. 6A-C are reproductions illustrating a comparison of direct and amplified array analysis wherein (A) illustrates the results for direct analysis using 100 ⁇ g total RNA, (B) illustrates the results obtained for direct analysis using 4 ⁇ g total RNA, and (C) illustrates the results for amplified analysis using 4 ⁇ g RNA.
  • an array-based binding assay incorporates an amplified reporter system utilized for the analysis of various materials including oligonucleotides, DNA and/or RNA and/or fragments thereof, peptides, protein fragments, cell fragments, cells and/or tissues.
  • an amplified reporter system means a system, in which the formation of one specific binding pair will give rise to a multitude of reporter species. This is in contrast to a nonamplified system such as a system wherein a fluorescently tagged antibody reacts with an appropriate antigen to form a specific binding pair which can include fluorescent tags or labels thereupon without generating any signal amplification from the formation of the specific binding pair.
  • One particularly preferred group of amplified reporter systems comprises enzymatically amplified reporter systems with catalyzed reporter deposition (CARD) being one particularly preferred amplification system.
  • CARD amplification is a novel method of signal amplification which is disclosed in U.S. Pat. 5,731,158; 5,583,001 and 5,196,306, the disclosures of which are incorporated herein by reference.
  • the method uses an analyte dependent enzyme activation system (ADEAS) to catalyze the deposition of reporter or hapten groups (labels) onto the solid phase of an assay support.
  • ADAS analyte dependent enzyme activation system
  • FIG. 1 depicts a support member 12 having an array of first members of a specific binding pair supported thereupon.
  • two members of the array 14 and 16 are depicted.
  • these members can comprise materials such as oligonucleotides, DNA and/or RNA and/or fragments thereof, peptides, protein fragments, cell fragments, cells and tissues and each is capable of binding to a specific material so as to form a specific binding pair.
  • the support member 12 may be polymeric or glass and may be in the form or shape of any solid or porous support, and it will include a number of receptor sites 18 thereupon.
  • receptor sites 18 function to bind an activated, labeled conjugate, as will be described hereinbelow.
  • the receptor sites 18 may comprise chemically active sites, such as phenolic sites normally present on the support member 12 , or they may comprise a material separately added to the support, such as a proteinaceous material, a phenolic based material, or any other such compound capable of interacting with the activated conjugate, as will be described hereinbelow, or the support surface itself may be chemically reactive.
  • FIG. 2 depicts a further stage in the use of the analytical system.
  • the array is contacted with a mixture which may include one or more second members of a specific binding pair, capable of binding to at least one of the immobilized first members on the support 12 .
  • the mixture includes two different second members 20 , 22 .
  • the second member 20 has bound to the immobilized first member 14 to form a specific binding pair 24 .
  • the other second member 22 is not capable of binding to either of the first members 14 , 16 , and does not form a specific binding pair, and in a subsequent step is washed away or otherwise removed from the region of the support member 12 .
  • an enzyme 26 is coupled to the specific binding pair 24 . While the Figures imply that the enzyme 26 is joined to the specific binding pair 24 after the specific binding pair is formed, the methodology of the present invention does not require this sequence of events. In some instances, the enzyme 26 may be coupled to the second member 20 prior to the formation of the binding pair, while in other instances, the enzyme 26 may be coupled after formation of the specific binding pair. Coupling can be accomplished by specific or nonspecific binding reactions. In some particular instances, the enzyme itself will be the second member of the specific binding pair, in which case, formation of the specific binding pair will inherently incorporate the enzyme.
  • an enzyme 26 will be immobilized upon the support member 12 only at those locations in the matrix at which a specific binding pair is formed.
  • the enzyme in one specific embodiment, comprises horseradish peroxidase (HRP), although other enzymes may be utilized in other embodiments of the invention.
  • the labeled conjugate 28 includes a substrate (S) for the enzyme 26 , and a label (L).
  • the substrate is a material which is activatable by the enzyme so as to cause it to bind to the receptor sites 18 on the support member 12 .
  • the receptor sites 18 may be reactive components of the support member 12 or may be added to the support member 12 .
  • the label can be any detectable label, such as a fluorescently detectable label, a hapten (e.g.
  • the enzyme 26 creates an activated conjugate 28 ′, and as seen in FIG. 5, this activated conjugate 28 ′ binds to the receptor sites 18 in the region of the specific binding pair 24 .
  • the unactivated conjugate 28 is not capable of binding to the receptor sites 18 ; hence, the label is displayed only proximate the specific binding pair 24 .
  • the formation of one specific binding pair 24 catalyzes the deposition of a number of labeled conjugates, thereby providing an amplified reporter system.
  • the methodology of the present invention may be implemented in accord with various array-based analyses of the type shown in the prior art including both layered and non-layered assays and incorporated hereinabove by reference.
  • Specific chemistries for the catalysts, supports, substrates, labels and members of the specific binding pair will depend upon the exact nature and purpose of the assays, which, in view of the teaching presented herein and in the patents referred to herein, will be readily apparent to one of skill in the art.
  • cyanine 5 labeled cDNA was prepared from 100 ⁇ g and 4 ⁇ g Jurkat total RNA using the MICROMAX Direct Reagent Kit (NEN Life Science Products, Boston, Mass.). The cyanine 5 labeled cDNA was hybridized to Practice Slides (MICROMAX Human cDNA Microarray System I, NEN Life Science Products, Boston, MA) a microarray system for differential gene expression analysis according to MICROMAX Human cDNA System I-Direct (NEN Life Science Products, Boston, Mass.) kit directions.
  • biotin labeled cDNA was prepared from 4 ⁇ g Jurkat total RNA using the MICROMAX Human cDNA Microarray System I kit reagents and protocols. Hybridization to Practice Slides and amplified detection using streptavidin-HRP and cyanine 5 tyramide were according to the MICROMAX Human cDNA Microarray System I kit directions.
  • FIG. 6 A The results for direct analysis using 100 ⁇ g total RNA are shown in FIG. 6 A.
  • FIG. 6B shows the results obtained for direct analysis using 4 ⁇ g total RNA.
  • FIG. 6 C The results for amplified analysis using 4 ⁇ g total RNA is shown in FIG. 6 C.
  • the loss of signal going from 100 ⁇ g to 4 ⁇ g of total RNA for direct analysis indicates that there is insufficient material available for adequate analysis. A greater amounts of cells or tissue mass is required for the direct method.
  • the signal for the amplified analysis using 4 ⁇ g of total RNA is greater than that using 100 ⁇ g for direct analysis, allowing for much greater flexibility in analyzing small amounts of tissues or cells.

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US09/430,429 1998-11-02 1999-10-29 Amplified array analysis system Expired - Lifetime US6399299B1 (en)

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Application Number Priority Date Filing Date Title
US09/430,429 US6399299B1 (en) 1998-11-02 1999-10-29 Amplified array analysis system
PCT/US1999/025616 WO2000026409A1 (fr) 1998-11-02 1999-11-01 Procede et systeme d'analyse a reseau amplifie
EP99971465A EP1127166A4 (fr) 1998-11-02 1999-11-01 Procede et systeme d'analyse a reseau amplifie
US10/123,713 US20020110846A1 (en) 1998-11-02 2002-04-16 Amplified array analysis method and system
US11/741,548 US8153367B2 (en) 1999-10-29 2007-04-27 Amplified array analysis system

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US10665398P 1998-11-02 1998-11-02
US09/430,429 US6399299B1 (en) 1998-11-02 1999-10-29 Amplified array analysis system

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020110846A1 (en) * 1998-11-02 2002-08-15 Perkinelmer Life Sciences, Inc. Amplified array analysis method and system
US20020192650A1 (en) * 2001-05-30 2002-12-19 Amorese Douglas A. Composite arrays
US20030232380A1 (en) * 2002-06-18 2003-12-18 Ayako Maruyama Probe array substrate for detecting target substrance
US20040038306A1 (en) * 2002-05-03 2004-02-26 Brian Agnew Compositions and methods for detection and isolation of phosphorylated molecules
US20040171034A1 (en) * 2002-05-03 2004-09-02 Brian Agnew Compositions and methods for detection and isolation of phosphorylated molecules
US20050014197A1 (en) * 2002-05-03 2005-01-20 Brian Agnew Compositions and methods for detection and isolation of phosphorylated molecules
US20050136534A1 (en) * 2003-10-24 2005-06-23 John Austin Apparatus and method for dispensing fluid, semi-solid and solid samples
US20070020681A1 (en) * 2003-06-12 2007-01-25 Perkinelmer Las, Inc. Hydrolytic substrates for an analyte-dependent enzyme activation system
US20070254308A1 (en) * 1999-10-29 2007-11-01 Perkinelmer Las, Inc. Amplified array analysis method and system
US9075055B2 (en) 2013-03-15 2015-07-07 Hycor Biomedical, Inc. Device and associated methods for performing luminescence and fluorescence measurements of a sample

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004040314A1 (fr) * 2002-10-31 2004-05-13 Chemometec A/S Procede d'evaluation de particules

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AU714486B2 (en) * 1995-11-21 2000-01-06 Yale University Unimolecular segment amplification and detection
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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020110846A1 (en) * 1998-11-02 2002-08-15 Perkinelmer Life Sciences, Inc. Amplified array analysis method and system
US8153367B2 (en) * 1999-10-29 2012-04-10 Perkinelmer Las, Inc. Amplified array analysis system
US20070254308A1 (en) * 1999-10-29 2007-11-01 Perkinelmer Las, Inc. Amplified array analysis method and system
US20020192650A1 (en) * 2001-05-30 2002-12-19 Amorese Douglas A. Composite arrays
US20060008836A1 (en) * 2001-05-30 2006-01-12 Amorese Douglas A Composite arrays
US20040038306A1 (en) * 2002-05-03 2004-02-26 Brian Agnew Compositions and methods for detection and isolation of phosphorylated molecules
US20050014197A1 (en) * 2002-05-03 2005-01-20 Brian Agnew Compositions and methods for detection and isolation of phosphorylated molecules
US20040171034A1 (en) * 2002-05-03 2004-09-02 Brian Agnew Compositions and methods for detection and isolation of phosphorylated molecules
US7102005B2 (en) 2002-05-03 2006-09-05 Molecular Probes, Inc. Compositions and methods for detection and isolation of phosphorylated molecules
US20070054304A1 (en) * 2002-05-03 2007-03-08 Invitrogen Corporation Compositions and methods for detection and isolation of phosphorylated molecules
US7776533B2 (en) 2002-05-03 2010-08-17 Life Technologies Corporation Compositions and methods for detection and isolation of phosphorylated molecules
US7445894B2 (en) 2002-05-03 2008-11-04 Molecular Probes, Inc. Compositions and methods for detection and isolation of phosphorylated molecules
US20030232380A1 (en) * 2002-06-18 2003-12-18 Ayako Maruyama Probe array substrate for detecting target substrance
US20070020681A1 (en) * 2003-06-12 2007-01-25 Perkinelmer Las, Inc. Hydrolytic substrates for an analyte-dependent enzyme activation system
US7291474B2 (en) 2003-06-12 2007-11-06 Perkinelmer Las, Inc. Hydrolytic substrates for an analyte-dependent enzyme activation system
US7585463B2 (en) 2003-10-24 2009-09-08 Aushon Biosystems, Inc. Apparatus and method for dispensing fluid, semi-solid and solid samples
US9527085B2 (en) 2003-10-24 2016-12-27 Aushon Biosystems, Inc. Apparatus and method for dispensing fluid, semi-solid and solid samples
US20050136534A1 (en) * 2003-10-24 2005-06-23 John Austin Apparatus and method for dispensing fluid, semi-solid and solid samples
US9753033B2 (en) 2013-03-15 2017-09-05 Hycor Biomedical, Llc Device and associated methods for performing luminescence and fluorescence measurements of a sample
US9651550B2 (en) 2013-03-15 2017-05-16 Hycor Biomedical, Llc Automated immunoanalyzer system for performing diagnostic assays for autoimmune and infectious diseases
US9658225B2 (en) 2013-03-15 2017-05-23 Hycor Biomedical, Llc Automated immunoanalyzer system for performing diagnostic assays for allergies and autoimmune diseases
US9658226B2 (en) 2013-03-15 2017-05-23 Hycor Biomedical, Llc Automated immunoanalyzer system for performing diagnostic assays for autoimmune and infectious diseases
US9075055B2 (en) 2013-03-15 2015-07-07 Hycor Biomedical, Inc. Device and associated methods for performing luminescence and fluorescence measurements of a sample
US9766233B2 (en) 2013-03-15 2017-09-19 Hycor Biomedical, Llc Device and associated methods for performing luminescence and fluorescence measurements of a sample
US10732111B2 (en) 2013-03-15 2020-08-04 Hycor Biomedical, Llc Automated immunoanalyzer system for performing diagnostic assays for allergies and autoimmune diseases
US10732110B2 (en) 2013-03-15 2020-08-04 Hycor Biomedical, Llc Automated immunoanalyzer system for performing diagnostic assays for autoimmune and infectious diseases
US10739262B2 (en) 2013-03-15 2020-08-11 Hycor Biomedical, Llc Automated immunoanalyzer system for performing diagnostic assays for autoimmune and infectious diseases
US10955346B2 (en) 2013-03-15 2021-03-23 Hycor Biomedical, Llc Device and associated methods for performing luminescence and fluorescence measurements of a sample
US11204323B2 (en) 2013-03-15 2021-12-21 Hycor Biomedical, Llc Device and associated methods for performing luminescence and fluorescence measurements of a sample

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US20020110846A1 (en) 2002-08-15
EP1127166A4 (fr) 2004-07-28
WO2000026409A9 (fr) 2001-09-27
WO2000026409A1 (fr) 2000-05-11
EP1127166A1 (fr) 2001-08-29
WO2000026409A8 (fr) 2001-02-08

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